Article Text

PDF
Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse
  1. K Komura1,2,
  2. M Fujimoto1,
  3. K Yanaba1,
  4. T Matsushita1,
  5. Y Matsushita1,
  6. M Horikawa1,
  7. F Ogawa2,
  8. K Shimizu2,
  9. M Hasegawa1,
  10. K Takehara1,
  11. S Sato2
  1. 1
    Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
  2. 2
    Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  1. Dr Shinichi Sato. Department of Dermatology Nagasaki University Graduate School of Biomedical Sciences. 1-7-1 Sakamoto Nagasaki 852-8501, Japan; s-sato{at}net.nagasaki-u.ac.jp

Abstract

Objective : To assess the association of CD40/CD40 ligand (CD40L) interactions with the development of skin fibrosis and autoimmunity in tight-skin (TSK/+) mouse, which is a mouse model for human systemic sclerosis.

Methods: Newly born TSK/+ mice were treated with murine anti-CD40L monoclonal antibody (100 μg intraperitoneally weekly). Hypodermal thickness of 8-week-old female mice (defined as the thickness of a subcutaneous loose connective tissue layer beneath the panniculus carnosus) was measured under a light microscope. All skin sections were taken from the para-midline, upper back region. Serum anti-topoisomerase I autoantibody levels, serum immunoglobulin levels and plasma soluble CD40L levels were determined by enzyme-linked immunosorbent assay. For analysis of lymphocyte surface molecules, single cell suspensions of lymphocytes were stained by monoclonal antibodies. Proliferation of TSK/+ B cells and fibroblasts to anti-CD40 antibodies was assessed by the uptake of [3H]-labelled thymidine and bromodeoxyuridine, respectively.

Results: The blockade of CD40/CD40L interactions by anti-CD40L monoclonal antibody significantly reduced cutaneous fibrosis (65%) and anti-topoisomerase I autoantibody in TSK/+ mice. Anti-CD40L monoclonal antibody also normalised B lymphocyte abnormal activation in TSK/+ mice, demonstrated by hyper-γ-globulinaemia. Furthermore, augmented CD40/CD40L interactions in TSK/+ mice were suggested by upregulated expression of CD40L on CD4+ T cells, elevated plasma soluble CD40L levels. The hyperresponsiveness to CD40 stimulation was also observed in TSK/+ B cells and fibroblasts.

Conclusions: Cutaneous fibrosis and autoimmunity in TSK/+ mice are closely correlated with CD40/CD40L interactions.

Statistics from Altmetric.com

Footnotes

  • Competing interests: None.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.